Utah's Connection to Cleft Palate

The faces in advertisements for the charities Operation Smile and The Smile Train are familiar to most Americans. The photographs show sad children whose faces are marked by cleft lips, sometimes even gaping openings between their mouths and noses that reveal misshapen palates and teeth that have grown askew. The “after” pictures show their surgically reconstructed smiles and beaming faces. We tend to think of them as the people who have cleft lip and cleft palate: poor and living in places like India, Guatemala, Rwanda or the Philippines.

Ron Munger — who has devoted much of his career in nutritional epidemiology to deciphering the causes of cleft lip and cleft palate — has spent time in several distant, developing nations. It turns out though that he has a large pool of prospective research subjects here at home. Utah has the highest recorded incidence of cleft lip and palate in the United States: 2.2 per 1,000 births, which is about double the average for Caucasian Americans and equal to the numbers in the Philippines.

It could be that rates are higher and just underreported in the Philippines, but we’re trying to understand why the numbers of recorded cases here are so similar,” Munger said. “I thought clefts occurred at higher rates in developing countries because of poverty and poor nutrition and those are likely to be important causes. But why are the numbers so high in Utah? That remains a mystery. Smoking is associated with clefts, but smoking rates are fairly low in Utah. Diabetes and obesity have been associated with clefts, but Utah is about average nationally in rates of diabetes and obesity. Utah mothers are, in general, well-educated and have far more resources than mothers in the Philippines, so we don’t understand why the rates in Utah are so high.”

Most people in the U.S. are less aware of cleft birth defects compared to those living in developing countries because clefts here are surgically repaired soon after birth. In Utah we don’t live near children with unrepaired clefts who struggle to eat, drink or speak because of cleft lips and palates or people who have grown to adulthood on the fringes of their communities because of their appearance. But the birth defect affects people everywhere and if Munger and his colleagues can discover the cause — or causes — thousands of surgeries on infants could be avoided each year.

During gestation, everyone begins with a cleft lip that typically closes between 6 and 8 weeks of fetal development. The palate follows, closing at 10 to 12 weeks. When they don’t close normally, the cleft remains. The causes of cleft lip and palate (CLP) are somewhat less mysterious than they were just a few decades ago. Scientists know maternal health, nutrition, genetics, and the environment are crucial parts of the puzzle. But each factor is complex on its own and understanding how each may be implicated in CLP means investigating them all and their interactions.

There are themes Munger’s research follows whether he is examining data from Utah or abroad. One is focused on nutrients in mothers’ diets. Another is whether mothers of children with CLP are more prone to developing diabetes or metabolic syndrome, a collection of metabolic disorders that includes a large waistline, high triglyceride level (a type of fat in the blood), low HDL “good” cholesterol level, high blood pressure and a high fasting level of blood sugar that can lead to diabetes, heart disease and stroke. A third area of interest is the possible connection to poor air quality.

Three nutrients are known to be related to CLPs and neural tube defects, which are birth defects of the brain, spine or spinal cord. Folate, vitamin B6 and zinc are all important to fetal devel- opment. A successful clinical trial that demonstrated folic acid supplements reduced the risk of neural tube defects led the U.S. Food and Drug Administration to mandate in 1998 that folic acid be added to flour. The ruling was a reaction to evidence from that study and the fact that birth defects occur so early in pregnancy that most expectant mothers are not taking prenatal vitamins during that critical stage of development. Munger said there is some indirect evidence that problems with folate nutrition may be at play in causing CLP.

He read of studies in Mexico, published the in medical journal The Lancet in the 1970s, that reported on tracking the health of women up to 30 years after they had given birth to babies with and without CLP. The mothers of cleft children developed diabetes at a much higher rate than mothers of unaffected children, but this difference between mothers was not apparent at the time they gave birth. Among the things Munger is examining is how blood folate levels change over time for women with and without cleft children. He has found some evidence that mothers of cleft children have increasingly lower blood folate levels over time, and suggests that this may be evidence of progressive metabolic disorder in folate metabolism, much like the Mexican mothers of cleft children who had progressively higher rates of another metabolic disorder—diabetes. With funding from the Centers for Disease Control and Prevention, Munger and colleagues from the Utah Birth Defects Network (Utah Department of Health) and the University of Utah are re-contacting mothers in Utah from their previous stud- ies to gather more data on folate metabolism, diabetes, and metabolic syndrome.

Munger is also working with colleagues in India and the Philippines on pilot studies funded by the U.S. National Institutes of Health to conduct similar studies of maternal nutrition and metabolic disorders that may be linked to clefts, work that will include surgeons and other staff with Operation Smile and Smile Train.

Munger said based on work he and his colleagues have already done, it appears that a mother’s whole dietary pattern is more strongly associated with the risk of having a child with a cleft than intake of any single nutrient. When asked about whether they took vitamins for the two months prior to becoming pregnant, twenty- five percent of women in the Utah study reported planning ahead and taking them.

“About half of women don’t know they are pregnant until the second month, so at that point the number of vitamin takers jumps to about fifty percent,” Munger said. “By the third and fourth months the number jumps again. But comparing vitamin intake at different times during pregnancy between mothers of children with clefts and without, showed no difference that we can detect in the Utah sample. However, a combination of taking prenatal vitamins and eating the DASH (Dietary Approaches to Stop Hypertension) diet shows about a fifty percent reduction of risk for clefts. The DASH diet includes an abundance of fruits and vegetables, whole grains, low-fat dairy products, and low intake of red meat and salt.”

His international work brought to Munger’s attention the pos- sibility of links between poor air quality and CLP. The incidence of children born with CLP is high in rural Asia and women there have among the world’s highest rates of lung disease, including lung cancer and chronic obstructive pulmonary disease (COPD), even if they are not tobacco smokers. It is also known that women who smoke have a forty percent increased risk of having a child with a cleft.

“Women in rural Asia are repeatedly exposed to cooking and heating fires in their homes,” Munger said. “Indoor air pollution is a huge concern, as is outdoor air pollution.”

Could Utah’s sporadically bad air quality be linked to the state’s high incidence of children born with clefts? That question prompted Munger’s current efforts to collaborate with USU Toxicology Professor Roger Coulombe who studies the adverse effects small particulate air pollution have on human cells and tissues.

In the lab, Coulombe and his associates incubate human lung cells and then expose them to PM 2.5 particles (meaning the particles are just 2.5 microns in diameter) that have been collected from polluted air. These particles are beyond tiny. To put 2.5 microns in perspective it helps to know that the diameter of a human hair is typically 50-70 microns. These particles — which often become trapped for days or weeks during the winter in northern Utah’s Cache Valley and along the state’s populous Wasatch Front — drastically reduce visibility and can make it painful to breathe. PM 2.5s are also small enough to pass directly into the bloodstream and cause damage. Coulombe has found lung cells react rapidly to the particles, becoming inflamed and increasing production of C-reactive protein which is linked to inflammation throughout the body which is associated with cardiovascular disease and adverse effects on maternal and child health. Because smoking is an established risk factor for clefts, Munger believes that indoor and outdoor air pollution are also potential causal factors, though to date this has not been adequately studied. Munger is working to develop studies of air pollution and clefts in India, the Philippines and Utah.

Though genes are a dominant force in human development and there are known genetic defects that result in clusters of many children affected with clefts in families, these are fairly rare. Yet, many have wondered if Utah has some genetic “difference” that could explain the high numbers of children with clefts.

The genetic makeup of Utah’s population is very well studied,” Munger said. “It turns out Utah has a very diverse mix of Northern European ancestry because its Caucasian population was founded by a large number of immigrants from Scandinavia, Germany, and the British Isles. Utah’s population was not founded by very small groups of people like the Amish or Mennonites, a situation that can result in a high frequency of deleterious genes. While some rare families have a high frequency of genes related to clefting, Munger believes that Utah’s high rate of clefting is not linked to large-scale genetic differences but rather is related to factors of lifestyle and environment.

As it is with most research, a simple question like, “What causes cleft lip and cleft palate?” has no simple answer. What scientists learn leads to more questions and to more investigations of what we don’t know. Though Munger knows dis- covering the roots of CLP will consume much of his attention, and that of other researchers even after he retires, he isn’t looking for something easier to explore. He isn’t a medical doctor, his work mostly involves detective work in interesting populations such as in India, the Philippines, and Utah. He works on deciphering moun- tains of data, and it is the experiences of seeing hundreds of faces of affected children, their families, and their living conditions that keeps him at it.

“I’m not a clinician,” he said. “I don’t do surgery and therefore I can’t do anything to immediately change the lives of the children I study. I can however design studies to collect data and examine new ideas. You can’t help but be motivated to find a way to help when you are there with these people and these problems are right in front of your eyes. You see how important this work could be to the children not yet born.” – LH